ScienceDaily (Feb. 29, 2012) — In a mouse model of Alzheimer’s disease, memory problems stem from an overactive enzyme that shuts off genes related to neuron communication, a new study says.

When researchers genetically blocked the enzyme, called HDAC2, they ‘reawakened’ some of the neurons and restored the animals’ cognitive function. The results, published February 29, 2012, in the journal Nature, suggest that drugs that inhibit this particular enzyme would make good treatments for some of the most devastating effects of the incurable neurodegenerative disease.

"It’s going to be very important to develop selective chemical inhibitors against HDAC2," says Howard Hughes Medical Institute investigator Li-Huei Tsai, whose team at the Massachusetts Institute of Technology performed the experiments. "If we could delay the cognitive decline by a certain period of time, even six months or a year, that would be very significant."

In every cell, DNA wraps itself around proteins called histones. Chemical groups such as methyl and acetyl can bind to histones and affect DNA expression. HDAC2 is a histone deacetylase, an enzyme that removes acetyl groups from the histone, effectively turning off nearby genes.

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A DRUG which minimises brain damage when given three hours after stroke has proved successful in monkeys and humans.

A lack of oxygen in the brain during a stroke can cause fatal brain damage. There is only one approved treatment - tissue plasminogen activator - but it is most effective when administered within 90 minutes after the onset of stroke. Immediate treatment isn’t always available, however, so drugs that can be given at a later time have been sought.

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke (Nature, DOI: 10.1038/nature10841).

An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results.

Source: New Scientist

ScienceDaily (Feb. 28, 2012) — Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained.

Slowing or preventing the development of Alzheimer’s disease, a fatal brain condition expected to hit one in 85 people globally by 2050, may be as simple as ensuring a brain protein’s sugar levels are maintained. (Credit: © ktsdesign / Fotolia)

That’s the conclusion seven researchers, including David Vocadlo, a Simon Fraser University chemistry professor and Canada Research Chair in Chemical Glycobiology, make in the latest issue of Nature Chemical Biology.

The journal has published the researchers’ latest paper “Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.”

Vocadlo and his colleagues describe how they’ve used an inhibitor they’ve chemically created — Thiamet-G — to stop O-GlcNAcase, a naturally occurring enzyme, from depleting the protein Tau of sugar molecules.

"The general thinking in science," says Vocadlo, "is that Tau stabilizes structures in the brain called microtubules. They are kind of like highways inside cells that allow cells to move things around."

Previous research has shown that the linkage of these sugar molecules to proteins, like Tau, in cells is essential. In fact, says Vocadlo, researchers have tried but failed to rear mice that don’t have these sugar molecules attached to proteins.

Vocadlo, an accomplished chess player in his spare time, is having great success checkmating troublesome enzymes with inhibitors he and his students are creating in the SFU chemistry department’s Laboratory of Chemical Glycobiology.

Research prior to Vocadlo’s has shown that clumps of Tau from an Alzheimer brain have almost none of this sugar attached to them, and O-GlcNAcase is the enzyme that is robbing them.

Such clumping is an early event in the development of Alzheimer’s and the number of clumps correlate with the disease’s severity.

Scott Yuzwa and Xiaoyang Shan, grad students in Vocadlo’s lab, found that Thiamet-G blocks O-GlcNAcase from removing sugars off Tau in mice that drank water with a daily dose of the inhibitor. Yuzwa and Shan are co-first authors on this paper.

The research team found that mice given the inhibitor had fewer clumps of Tau and maintained healthier brains.

"This work shows targeting the enzyme O-GlcNAcase with inhibitors is a new potential approach to treating Alzheimer’s," says Vocadlo. "This is vital since to date there are no treatments to slow its progression.

"A lot of effort is needed to tackle this disease and different approaches should be pursued to maximize the chance of successfully fighting it. In the short term, we need to develop better inhibitors of the enzyme and test them in mice. Once we have better inhibitors, they can be clinically tested.

Source: Science Daily

Yale University researchers have discovered a key cellular mechanism that may help the brain control how much we eat, what we weigh, and how much energy we have.

The findings, published in the Feb. 28 issue of the Journal of Neuroscience, describe the regulation of a family of cells that project throughout the nervous system and originate in an area of the brain call the hypothalamus, which has been long known to control energy balances.

Scientists and pharmaceutical companies are closely investigating the role of melanin-concentrating hormone (MCH) neurons in controlling food intake and energy. Previous studies have shown that MCH makes lab animals eat more, sleep more, and have less energy. In contrast, other hypothalamic neurons use the thyrotropin-releasing hormone (TRH) as a neurotransmitter, and these neurons reduce food intake and body weight, and increase physical activity.

The Yale study of brains of mice shows that the two systems appear to act in direct opposition, to help the organism keep these crucial functions in balance.

Although TRH is normally an excitatory neurotransmitter, the Yale study shows that in mice TRH inhibits MCH cells by increasing inhibitory synaptic input. In contrast, TRH had little effect on other types of neurons also involved in energy regulation.

“That these two types of neurons interact at the synaptic level gives us clues as to how the brain controls the amount of food we eat, and how much we sleep,” said Anthony van den Pol, senior author and professor of neurosurgery at Yale School of Medicine.

Three MCH neurons in the hypothalamus region of a mouse brain are highlighted in green. In animals, these neurons are associated with high calorie intake and lower energy levels. Yale researchers have shown how the effects of these key cells are reversed. Image adapted from Yale press release image.

Source: Neuroscience News

By SUSAN GREENFIELD

Human identity, the idea that defines each and every one of us, could be facing an unprecedented crisis. It is a crisis that would threaten long-held notions of who we are, what we do and how we behave. It goes right to the heart -or the head- of us all. This crisis could reshape how we interact with each other, alter what makes us happy, and modify our capacity for reaching our full potential as individuals. And it’s caused by one simple fact: the human brain, that most sensitive of organs, is under threat from the modern world.

PROFESSOR SUSAN GREENFIELD

Unless we wake up to the damage that the gadget-filled, pharmaceutically-enhanced 21st century is doing to our brains, we could be sleepwalking towards a future in which neuro-chip technology blurs the line between living and non-living machines, and between our bodies and the outside world.

It would be a world where such devices could enhance our muscle power, or our senses, beyond the norm, and where we all take a daily cocktail of drugs to control our moods and performance.

Already an electronic chip is being developed that could allow a paralysed patient to move a robotic limb just by thinking about it. As for drug manipulated moods, they’re already with us - although so far only to a medically prescribed extent.

Increasing numbers of people already take Prozac for depression, Paxil as an antidote for shyness, and give Ritalin to children to improve their concentration. But what if there were still more pills to enhance or “correct” a range of other specific mental functions?

Read more: Daily Mail

Article Date: 27 Feb 2012 - 10:00 PST

In a study, due to appear in the March 30 issue of Cell, researchers at MIT’s Picower Institute for Learning and Memory have discovered, for the first time, that neurons at different stages of their life cycles potentially perform two separate functions, such as forming distinct memories of almost identical situations, and the ability to recall an entire event when prompted by a tiny detail.

The study describes a brain structure that produces new neurons in adults as a possible vital target for developing drugs for the treatment of memory disorders. 


Lead author, Toshiaki Nakashiba at the Picower Institute said that an imbalance between young and old neurons in the brain region, called dentate gyrus can potentially disrupt memory formation, recalling and potentially affect cognitive dysfunctions related to post-traumatic stress disorder (PTSD), as well as aging. In dentate gyrus, only one of the two brain sites continuously generates new neurons throughout adult life.

Co-author Susumu Tonegawa, Picower Professor of Neuroscience at the Picower Institute explained:

"In animals, traumatic experiences and aging often lead to decline of the birth of new neurons in the dentate gyrus. In humans, recent studies found dentate gyrus dysfunction and related memory impairments during normal aging."

The brain detects small differences between similar experiences by pattern separation. Humans are able to recall explicit content of earlier memories with only limited clues related to the original experience when these patterns are complete. For instance, a person who has dinner at the same French restaurant two nights in a row makes similar experiences or observations on both occasions, like the menu, the surroundings, the time of their visit, etc.

The distinct memories that the person’s brains forms for each event are called pattern separation. If a friend, for instance, mentions a liking for onion soup some time later, the person may recall not only the dish they had at the restaurant, but the entire experience of which people were at the restaurant, what they did after the meal, etc. This process is recalled by pattern completion. 


Whilst pattern separation forms a unique new memory based on differences between experiences, pattern completion recalls memories by identifying similarities. People who have suffered severe brain injury or trauma are often unable to recognize their family and friends’ faces that they see on a regular basis, whilst others with PTSD are unable to forget harrowing events.

Tonegawa explains:

"Impaired pattern separation due to loss of young neurons may shift the balance in favor of pattern completion, which may underlie recurrent traumatic memory recall observed in PTSD patients."

For a long time, neuroscientists believed that these two opposing and competing processes occur in different neural circuits within the hippocampus, thinking that the dentate gyrus, a structure of significant interest for its plasticity within the nervous system and its impact on conditions ranging from depression and epilepsy to traumatic brain injury, is involved in pattern separation, whilst the CA3 region is involved in pattern completion. However, the MIT researchers discovered that the neurons spawned by the dentate gyrus alone could potentially have distinct roles as they age.

The MIT researchers explored a pattern separation in mice that learned to distinguish between two chambers, of which one was safe and the other gave them an unpleasant shock to their feet. To assess the mice pattern completion abilities, the researchers gave the mice limited cues in finding their way out of a maze they knew how to negotiate earlier. They compared normal mice with mice that lacked young or old neurons, and discovered that the mice exhibited defects in pattern completion or separation, depending on which set of neurons was depleted. Previous research supported the idea that the dentate gyrus or young neurons performed pattern separation when examining pattern separation, by manipulating the entire dentate gyrus or only adult-born young neurons.

Nakashiba concluded:

"By studying mice genetically modified to block neuronal communication from old neurons—or by wiping out their adult-born young neurons—we found that old neurons were dispensable for pattern separation, whereas young neurons were required for it. Our data also demonstrated that mice devoid of old neurons were defective in pattern completion, suggesting that the balance between pattern separation and completion may be altered as a result of loss of old neurons."

Written by Petra Rattue  

Source: Medical News Today

ScienceDaily (Feb. 27, 2012) — Most of us know what it means when it’s said that someone is depressed. But commonly, true clinical depression brings with it a number of other symptoms. These can include anxiety, poor attention and concentration, memory issues, and sleep disturbances.

Brain hyperactivity. Maps showing the difference in the strength of brain connections between depressed subjects (left) and controls (right). Depressed subjects show much stronger connections, as evidenced by red colors in their maps. (Credit: Image courtesy of University of California - Los Angeles)

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Debora A Rothmond, Cynthia S Weickert and Maree J Webster

BMC Neuroscience 2012, 13:18 doi:10.1186/1471-2202-13-18 Published: 15 February 2012           

Background

Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-O-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).

Results

Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p<0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p<0.001) and D2L (p=0.003) isoforms, monoamine oxidase A (p<0.001) and catechol-O-methyltransferase (p=0.024) were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32kDa, p=0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p=0.002) and dopamine D1 receptor protein expression increased throughout development (p<0.001) with adults having the highest D1 protein levels (p[less than or equal to]0.01). Monoamine oxidase B mRNA and protein (p<0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r=-0.31, p=0.018) in an expression profile opposite to that of the dopamine D1 receptor.

Conclusions

We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function. 

Source: BMC Neuroscience

February 24, 2012 by Stuart Mason Dambrot

Mechanisms of fluorescent voltage sensing. (A) Electrochromic voltage-sensitive dyes (VDSs) sense voltage when the chromophore interacts directly with the electric field. Changes in the energy levels of the chromophore result in small spectral shifts in the emission of the dye. (B) Fluorescence resonance energy transfer-pair voltage sensors use lipophilic anions (red). Depolarization causes translocation of the anion, which can now quench the fluorescence of an immobilized fluorophore (green). (C) Molecular wire photo-induced electron transfer (PeT) VSDs depend upon the voltage-sensitive electron transfer from an electron-rich donor (orange) through a membrane-spanning molecular wire (black) to a fluorescent reporter (green). Image Copyright © PNAS, doi: 10.1073/pnas.1120694109

(Medical Xpress) — Optically monitoring the brain’s neuronal activity can be accomplished in several ways, including electrochromic dyes, hydrophobic anions, calcium imaging, or voltage-sensitive ion channels. Fluorescence imaging is an attractive method due to its ability to map the electrical activity and communication of multiple spatially resolved neurons. While this complements traditional electrophysiological measurements, historically fluorescent voltage imaging has been limited by the difficulty of developing sensors that give both large and fast responses to voltage changes. Recently, however, scientists in the Department of Pharmacology and other areas in the University of California at San Diego’s Howard Hughes Medical Institute have designed, synthesized, and implemented fluorescent sensors in the form of photo-induced electron transfer (PeT)-based molecular wire probes for voltage imaging in neurons. Moreover, they have used these so-called VoltageFluor sensors to perform single-trial detection of synaptic and action potentials in cultured hippocampal neurons and intact leech ganglia.

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Article Date: 24 Feb 2012 - 8:00 PST

A new study, in this week’s online edition of the Proceedings of the National Academy of Sciences , shows an incredible degree of biological diversity in a surprising location, i.e. in a single neural connection in the body wall of flies. The finding opens up a new spectrum of interesting questions regarding the importance of the nervous system structure and the evolution of neural wiring.

Geneticist Barry Ganetzky, Steenbock Professor of Biological Sciences at the University of Wisconsin-Madison declared:

 ”We know almost nothing about the evolution of the nervous system, although we know it has to happen - behaviors change, complexity changes, there is the addition of new neurons, formation of different synaptic connections.”

The finding proves even more astounding given that Ganetzky and his graduate student Megan Campbell discovered the unexpected diversity in a location very familiar to scientists, i.e. the neuromuscular junction 4 (NMJ4), the location where a single motor neuron contacts a particular muscle in the fly body wall to drive its activity. The synapses where neurons link to their neuronal or muscular targets have a complex structural form, looking like miniature trees decorated with tiny bulbs that are the nerve terminals (synaptic boutons).

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